Tissue macrophages are cells produced by the differentiation of monocytes in tissues in response to microenvironmental factors such as M-CSF (macrophage colony-stimulating factor), GM-CSF (granulocyte macrophage colony-stimulating factor), or IL3 during extravascularization. (Serbina, et al. 2008 Annu Rev Immunol 26:421-452.) Macrophages play critical roles in both innate and adaptive immunity in virtually all tissues. (Auffray, et al. 2009 Annu Rev Immunol 27:669-692; Martinez, et al. 2008 Front Biosci 13:453-461; Mosser, et al. 2008 Nat Rev Immunol 8:958-969.)
The process of monocyte to macrophage terminal differentiation remains a subject of extensive investigation in the contexts of immune defense against pathogen invasion, pathogenesis of autoimmune and inflammatory diseases, and carcinogenesis of hematopoietic and other malignancies. (Tenen 2003 Nat Rev Cancer 3:89-101.) Upon differentiation, the function of macrophages can be further activated by extracellular signals and displays diverse patterns depending upon the cytokines and microbial products present in the microenvironment.
Macrophage activation has been classified into a classical pathway and an alternative pathway. In response to Th1 cytokines, such as interferon γ (IFN-γ) and lipopolysaccharide (LPS), macrophages display a classical activation phenotype and produce mainly pro-inflammatory cytokines. The Jak/Stat and AP-1/NFκB signaling pathways have been shown to play critical roles in classical activation of macrophages. Alternatively, macrophages can be activated by Th2 cytokines, such as IL4 or IL13, and exhibit distinct functions with anti-inflammatory and tissue repair properties. (Martinez, et al. 2008 Front Biosci 13:453-461; Mosser, et al. 2008 Nat Rev Immunol 8:958-969; Gordon 2003 Nat Rev Immunol 3:23-35; Schroder, et al. 2006 Immunobiology 211:511-524.)
The common myeloid progenitor cells are the bone marrow precursors of monocytes and macrophages. It is generally accepted that monocyte and macrophage development occurs by changes of transcriptional programs in a stepwise manner. (Friedman 2007 Oncogene 26:6816-6828; Friedman 2002 Oncogene 21:3377-3390; Valledor, et al. 1998 J Leukoc Biol 63:405-417; Tenen, et al. 1997 Blood 90:489-519.) Genetic studies with knockout mice have revealed the important roles of transcription factors such as PU.1 and C/EBPα in monocyte/macrophage lineage commitment. (Yeamans, et al. 2007 Blood 110:3136-3142; Scott, et al. 1994 Science 265:1573-1577; McKercher, et al. 1996 Embo J 15:5647-5658.)
Recently, global transcriptome analysis revealed profound changes in gene expression during monocyte to macrophage terminal differentiation. (Liu, et al. 2008 Immunol Lett 117:70-80; Martinez, et al. 2006 J Immunol 177:7303-7311.) Previous studies on human monocyte to macrophage differentiation have mainly relied on myeloid progenitor cell lines like U937 and THP-1. (Lu, et al. 2001 J Biol Chem 276:45491-45496; Chang, et al. 2000 Nat Immunol 1:169-176; Liu, et al. 1996 Genes Dev 10:142-153.) The key transcriptional mechanism controlling primary human monocyte to macrophage differentiation remains poorly defined.
Developmental modeling is informative in defining genes and pathways involved in host defense and immune regulation. Using methods of reverse genetics, it was recently demonstrated that VentX, a human homologue of the Xenopus homeobox transcriptional factor Xom, is a LEF/TCF-associated Wnt repressor and a putative tumor suppressor. (Gao, et al. 2010 Cancer Res 70:202-211; Gao, et al. 2007 Cell Res 17:345-356; U.S. Pat. No. 7,994,126, expressly incorporated herein by reference for all purposes; WO/2011/00894, PCT/US2010/042126, expressly incorporated herein by reference for all purposes.) Also shown was that VentX trans-activates p53/p21 and p16ink4a/Rb pathways to regulate senescence in tumor cells. (Wu, et al. 2011 J Biol Chem 286:12693-12701) VentX is predominantly expressed in hematopoietic cells and highly conserved in primates. However, researches have failed to identify the murine homologue of VentX in the current mouse genome database (20, 23, 24). (Gao, et al. 2010 Cancer Res 70:202-211; Ku, et al. 2006 J Biol Chem 281:5277-5287; Rawat, et al. 2010 Proc Natl Acad Sci USA 107:16946-16951.)
Therefore, a continued need exists for better understanding of the role of VentX, in particular in relation to microphage differentiation and activation, and therapeutic and/or diagnostic applications based therefrom.